The stereoselective preparation of substituted pyrrolidines using titanium- And zirconium-mediated diene metallabicyclisation methodology: The total synthesis of (-)-α-kainic acid

Article abstract of DOI:10.1039/b005853j

Zirconium- and titanium-mediated diene metallabicyclisation-elimination-functionalisation have been compared, contrasted and utilised for the preparation of 3,4-disubstituted and 2,3,4-trisubstituted pyrrolidines in high yield and excellent stereoselectivity. The zirconium-mediated methodology has been employed as the key step in a partial synthesis of (-)-α-kainic acid starting from D-serine, but the key metallabicyclisation sequence proceeded with poor stereocontrol. By contrast, the total synthesis of (-)-α-kainic acid starting from L-serine was accomplished using a titanium-mediated cyclisation sequence which proceeded with excellent stereocontrol. Novel kainoids and piperidines are also reported. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b005853j

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The stereoselective preparation of substituted pyrrolidines using
titanium- and zirconium-mediated diene metallabicyclisation
methodology: the total synthesis of (؊)-ꢀ-kainic acid
1
Andrew D. Campbell,a Tony M. Raynhamb and Richard J. K. Taylor*a
a Department of Chemistry, University of York, York, UK Y010 5DD. E-mail: rjkt1@york.ac.uk
b Roche Discovery Welwyn, Welwyn Garden City, Hertfordshire, UK AL7 3AY
Received (in Cambridge, UK) 20th July 2000, Accepted 8th August 2000
First published as an Advance Article on the web 18th September 2000
Zirconium- and titanium-mediated diene metallabicyclisation–elimination–functionalisation have been compared,
contrasted and utilised for the preparation of 3,4-disubstituted and 2,3,4-trisubstituted pyrrolidines in high yield
and excellent stereoselectivity. The zirconium-mediated methodology has been employed as the key step in a partial
synthesis of (Ϫ)-α-kainic acid starting from -serine, but the key metallabicyclisation sequence proceeded with poor
stereocontrol. By contrast, the total synthesis of (Ϫ)-α-kainic acid starting from -serine was accomplished using a
titanium-mediated cyclisation sequence which proceeded with excellent stereocontrol. Novel kainoids and piperidines
are also reported.
(Ϫ)-α-Kainic acid 1 has a highly functionalised trisubstituted
Scheme 1
introduce the requisite 3-carboxymethyl substituent of the
kainoids.
Other cyclisation–elimination approaches to the kainoids
have been investigated but stereochemical control has been
poor.14 We felt that the approach outlined in Scheme 1 was
worthy of study, however, particularly as Takahashi et al.15 had
shown that cis-3,4-disubstituted pyrrolidines can be formed
using the zirconocene metallabicyclisation of 1,6-dienes con-
taining a terminal allylic ether (Scheme 2): it was proposed that
pyrrolidine skeleton with three contiguous chiral centres.1 The
C-2–C-3 arrangement is trans while the C-3–C-4 substituents
are in the thermodynamically less favourable cis-configuration.
(Ϫ)-α-Kainic acid 1 was first isolated from the marine algae
Digenea simplex2 along with its C-4 epimer α-allokainic acid 2.
In later work, kainic acid was obtained from the marine algae
Centrocerus clavulatum3 and from the Corsican moss Alsidum
helminthocorton.4 The potent neuroexcitatory activity of kainic
acid has generated enormous interest,1 but it also possesses
insecticidal5 and anthelmintic6 activity. With the discoveries of
the bioactive domoic acid7 and acromelic acid8,9 families (e.g.
domoic acid 3 and acromelic acid A 4), the synthetic com-
munity has been stimulated to design efficient, stereocontrolled
routes to 2,3,4-trisubstituted pyrrolidines.1,10
Scheme 2
the intermediate cis-3,4-zirconabicycle was kinetically preferred
and that equilibration to the trans-isomer was minimised by the
rapid elimination of the β-phenoxy group.
Despite this encouraging precedent, several questions
remained, particularly: (i) will the C-2 substituent affect the
efficiency of cyclisation, (ii) will the C-2 substituent direct
cyclisation to produce the required 2,3-trans-arrangement of
substituents and will the 3,4-cis-arrangement of substituents
predominate, (iii) will cyclisation occur on to the sterically
demanding trisubstituted alkene, (iv) will the recently
Given our own interest in the kainoid area,11 and our
ongoing research into synthetic applications of zirconium-
mediated diene cyclisation reactions,12 we envisaged a new
approach to kainic acid as shown in Scheme 1. Thus,
zirconium-mediated metallabicyclisation13 of dienes 5 should
produce metallabicycles 6 which would be expected to undergo
rapid β-elimination to generate the archetypal kainoid 4-
isopropenyl substituent. This sequence would produce alkyl-
organometallic reagents 7 which could then be functionalised to
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J. Chem. Soc., Perkin Trans. 1, 2000, 3194–3204
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b005853j

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Table 1 Model metallabicyclisation studies
Zr() Yield (%);
cis:trans
Ti() Yield (%);
cis:trans
Entry no.
Starting diene
Major product
Electrophile
i
Hϩ
50; 1:1
—
ii
Hϩ
Br2
69; 3:1
—
81; 3:1
47; 3:1
95; 6:1
67; 6:1
72; 6:1
0
I2
nBuNC
iii
iv
Hϩ
59; 10:1
74; 25:1
83; cis only
85; cis only
Hϩ
described16 titanium()-mediated metallabicyclisation method-
ology be superior to the zirconium procedure illustrated, and
(v) will it be possible to elaborate alkylorganometallic reagents
7 to give kainic acid?
Model studies were therefore carried out to assess the viabil-
ity of this new approach to the kainoids17 whilst comparing
and contrasting the Zr() and Ti() methodologies for the
synthesis of substituted pyrrolidines.
selectivity. Molecular modelling studies are in progress to
explain this enhanced selectivity, but it may be that the elimin-
ation to form the C-4 isopropene unit is faster than the
elimination to form the monosubstituted alkene (entry ii),
hence minimising equilibration.
We next studied the reactions of diene 15 to assess the effect
of a C-2 substituent on the metallabicyclisation process
(Scheme 3).
Results and discussion
Cyclisation precursors 8–11, utilised in the model metalla-
bicyclisation studies to investigate C-3–C-4 stereoselectivity
(Table 1), were readily prepared by alkylation of N-allyl-N-
benzylamine18 with the corresponding allyl chloride in the
presence of potassium carbonate and catalytic sodium iodide in
refluxing acetonitrile.
Initial studies were carried out using Negishi’s zirconocene
equivalent (ZrCp2Cl2–2 BuLi).13 As expected,13,15 zirconium-
mediated cyclisation of (2E)-N-benzyl-N-allylbut-2-en-1-amine
8 (Table 1, entry i) resulted in a 1:1 mixture of cis- and trans-
diastereomers 12 after protonation. However, with diene 9 bear-
ing a phenoxy leaving group (entry ii), zirconium-mediated
diene cyclisation–elimination–protonation proceeded smoothly
giving 13a as a 3:1 cis:trans mixture. It seems likely15 that
elimination occurs before significant equilibration from the
kinetically preferred cis-metallocycle to the thermodynamic-
ally-preferred trans-product can occur.19,20 We next compared
the cyclisation–elimination–protonation sequence using the
same diene 9, but employing Sato’s titanium procedure
[Ti(OPri)4–2 iPrMgCl]16 as shown in Table 1, entry ii: with this
reagent 13a was obtained in improved yield (95%) and with
better stereoselectivity (cis:trans = 6:1).17 Furthermore, we
were able to trap the alkyl zirconium or titanium organo-
metallic intermediate with electrophiles (entry ii) giving a range
of substituted pyrrolidines 13b–d. Of note is that quenching the
alkyl zirconium intermediate with n-BuNC gives the corre-
sponding aldehyde 13d as the only product after acidic work up,
but no reaction is observed with the corresponding titanium
reagent.
Scheme 3
Cyclisation of diene 15 using “ZrCp2” does not proceed with
the same efficiency or diastereocontrol as the previous model
systems in Table 1. Thus, although the major product 16 had
the kainoid configuration, three more diastereomers were also
isolated. The low yield and poor stereocontrol could indicate
that the C-2 substituent prevents efficient coordination of
zirconium to the terminal alkene and that, at least in part,
initial zirconium complexation is occurring at the more electron
rich trisubstituted alkene.
We next investigated the titanium-mediated cyclisation–
elimination reaction of 15. We were delighted to observe that,
in this case, the high C-3–C-4 cis-selectivity observed in the
earlier model studies was retained, and only the two separable
diastereoisomers 16 and 17 were isolated. The stereochemical
Cyclisation of the trisubstituted alkenes 10 and 11 to give 14
was investigated next (Table 1, entries iii and iv) and found to
proceed efficiently with a much higher cis-selectivity with both
reagents, the titanium process occurring with total stereo-
1
assignments were confirmed by comparison of the H-NMR
spectra of 16 and 17 with 13a and related systems,15 and by
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NOE studies (e.g. H-2 and H-4 enhanced by irradiation at H-3).
It is not entirely clear why the major product is the cis,cis-
pyrrolidine 17, although we assume that the smaller size of the
titanium reagent allows efficient coordination to the terminal
alkene, and it may be that intramolecular nitrogen to titanium
coordination is involved. It should be noted that during the
course of our studies Sato et al. also reported the stereoselective
synthesis of a 2,3,4-trisubstituted pyrrolidine via titanium-
mediated diene metallabicyclisation,16b although their system
was not suitable for elaboration to produce kainoids.
would be expected to produce mainly the cis,cis-pyrrolidine 23
with the kainoid C-3–C-4 cis-arrangement, subsequent inver-
sion of configuration at C-2 being required to complete the
natural product synthesis.
There are published examples of all cis-analogues of kainic
acid undergoing epimerisation at C-2 to give the kainoid struc-
ture.24 We therefore decided to explore a titanium-mediated
metallabicyclisation approach to kainoids. It should be noted
that a C-2 inversion strategy requires the use of the S-Garner
aldehyde 24 as starting material (Scheme 6).
Synthesis of (؊)-ꢀ-kainic acid
The results detailed in Scheme 3 above indicated that the
zirconium-mediated route could be employed to prepare kain-
oids, although the metallabicyclisation process seemed likely
to be inefficient. This was confirmed as part of a formal total
synthesis of kainic acid 1 (Scheme 4). Thus, the R-Garner alde-
t
Scheme
6
Reagents and conditions: (TBS = Me2 BuSi) (a) Ph3-
PϩCH3BrϪ, KHMDS, THF, Ϫ78 ЊC to rt (80%); (b) 6 M HCl (100%);
(c) (1) PhCHO, Et3N, Na2SO4, DCM, ∆, (2) NaBH4, MeOH, 0 ЊC, (3)
TBSCl, imidazole, DMF (70%); (d) 26, K2CO3, cat. NaI, MeCN (86%).
Thus, -Serine was converted into the S-Garner aldehyde
24 using our improved procedure.21 Wittig methylenation21 and
acid hydrolysis gave vinylglycinol hydrochloride 25. Reduc-
tive amination using benzaldehyde followed by O-silylation
furnished a secondary amine which was N-alkylated with
allyl chloride 26 to produce cyclisation precursor 27 in 60%
yield over 4 steps from 24. Allyl chloride 26 was prepared
by Horner–Wadsworth–Emmons elaboration of 2-phenoxy-
acetone with methyl diethylphosphonoacetate (94%, E:Z =
2:1) followed by chromatographic separation, reduction of the
resulting α,β-unsaturated ester (DIBAL) and chlorination
(TsCl, DMAP).
Scheme 4
hyde 18, readily prepared from -serine,21 was converted
into diene 19 via a straightforward six step sequence (see
later). Zirconium-mediated metallabicyclisation–elimination–
iodination gave a mixture of diastereomeric products, as
expected, with the kainoid precursor 20 predominating. Lithi-
ation followed by ethoxycarbonylation gave adduct 21 which
can be converted into kainic acid 1 via published22,23 procedures
(6 steps, 30% overall yield).
The Ti() mediated cyclisation–iodination of 27 was investi-
gated next (Scheme 7) and found to proceed in excellent yield
Thus, a formal total synthesis of kainic acid had been
achieved using zirconium methodology but the route was
marred by the low stereoselectivity of the metallobicyclisation
step. The titanium-mediated process shown in Scheme 3
showed much greater stereoselectivity than the corresponding
zirconium reaction, but the major product was a cis,cis-
pyrrolidine. Thus, the original analysis (Scheme 1) needed to be
revised as shown in Scheme 5: the enantiomeric C-2 system 22
Scheme 7 Reagents and conditions: (a) (1) Ti(O-i-Pr)4 ϩ 2 i-PrMgCl,
Et2O, Ϫ50 ЊC to rt, (2) I2, 0 ЊC (70%); (b) tBuLi (2.2 eq.), Et2O, Ϫ80 ЊC
then excess ClCO2Me, Ϫ80 ЊC, then ∆, 2 h (71%); (c) cat. TsOH,
MeOH, rt (100%).
and, in this case, with complete stereoselectivity to give 28 with
the expected cis,cis-geometry. Evidence for the stereochemistry
of 28 was obtained by NMR analysis and by lithiation followed
by trapping with ethyl chloroformate: the resultant ethyl ester
Scheme 5
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displayed different NMR characteristics to the known22 C-2
epimer 21. Lithium–halogen exchange and quenching with
excess methyl chloroformate followed by heating gave the ester
with concomitant N-benzyl cleavage–urethane formation to
produce 29 in 71% overall yield (N-benzyl protection can be
retained if the reaction is quenched at low temperature). The
next task was to convert the C-2 substituent into a carboxylic
acid derivative prior to epimerisation. Unfortunately, and per-
haps unsurprisingly, cleavage of the TBS group resulted in
facile cyclisation between the C-2 and C-3 side chains to
produce lactone 30. Numerous attempts (including cyanide
addition to iodide 28 and Jones’ oxidation of lactone 30) were
made to overcome this problem but without success.
overall yield. Jones’ oxidation cleaved the acetal and oxidised
the resulting aldehyde to produce the corresponding acid which
was treated with diazomethane to produce ester 36. Compound
36 is a protected derivative of the so-called β-kainic acid: the
titanium methodology provides a very convenient and stereo-
selective route to these compounds which are reported to have
interesting anti-convulsant properties.26
Epimerisation of 36 at C-2 was successfully achieved using
LiHMDS (2.5 eq.) and quenching with MeOH.24a Using this
procedure, complete conversion into the epimeric ester 37 was
observed [TLC (SiO2: EtOAc–light petroleum, 1:2) 36, Rf
0.30; 37,27 Rf 0.31]. Saponification of 37 was accompanied by
N-deprotection giving (Ϫ)-α-kainic acid 1, which was spectro-
scopically consistent with authentic material and corresponded
well in terms of polarimetry {[α]D Ϫ15.2 (c 0.95, H2O); lit.23 [α]D
Ϫ15.0 (c 0.5, H2O)} and mp (mp 244–247 ЊC dec.; lit.23 mp
237–243 ЊC dec.).
Therefore it was decided to carry out the metallabicyclisation
sequence with the C-2 substituent protected as a masked alde-
hyde (Scheme 8). The requisite diene 33 was prepared from the
Synthesis of novel pyrrolidines and piperidines
Having succeeded with two syntheses of kainic acid, we
attempted to extend the diene-cyclisation methodology to
produce novel C-4 substituted pyrrolidines and disubstituted
piperidines. The results are summarised in Table 2.
In an attempt to extend the methodology to novel analogues
of acromelic acid A 4, the metallabicyclisation reactions of the
cyclohexyl substituted diene 38 were studied (Table 2, entry i).
Again the zirconium- and titanium-mediated cyclisation pro-
cesses proceeded well with excellent cis-selectivity to give the
novel cyclohexenyl product 39 after protonation. We had hoped
to produce the corresponding aryl analogue 41 by metalla-
bicyclisation–elimination–aromatisation of diene 40 (entry ii).
Unfortunately, no cyclised product was isolated from either the
zirconium or titanium-mediated protocols.
We also carried out a preliminary study to look at piperidine
synthesis using metallabicyclisation.15,16,19 Cyclisation–proton-
ation of diene 42 using “ZrCp2” gave a mixture of cis- and trans-
43 and 44 but excellent cis-selectivity was again observed using
the titanium methodology (entry iii). Finally (entry iv), the
metallabicyclisation of diene 45 prepared from (R)-2-methyl-
benzylamine using the titanium methodology gave complete
cis-C-3–C-4 diastereoselectivity but no asymmetric induction
(as expected from earlier enyne studies by Sato et al.16b).
Conclusions
In conclusion, we have developed a new enantioselective syn-
thesis of (Ϫ)-α-kainic acid 1 which has as its cornerstone a
totally stereoselective titanium-mediated diene metallabicyclis-
ation process. The total synthesis is high yielding (3.5% in 12
steps from commercially available material). This new route
contrasts to other cyclisation–elimination approaches to the
kainoids where stereochemical control has been poor,14 and
although our procedure does require epimerisation at C-2 to
obtain the kainoid structure, it also provides a potential route
to β-kainoids. In addition, kainoid analogues with a range of
different substituents at C-3 and C-4 are available via this route.
From a general methodological viewpoint, the new procedure
for the stereoselective preparation of cis-3,4-di- and cis,cis-
2,3,4-trisubstituted pyrrolidines and cis-3,4-disubstituted
piperidines is noteworthy.
Scheme 8 Reagents and conditions: (a) Ph3PϩCH3BrϪ, KHMDS,
THF, Ϫ78 ЊC (80%); (b) Dowex (Hϩ) resin, aq. MeOH (93%); (c) Dess–
Martin oxidation; (d) HCl–MeOH; (e) PhCHO, NaBH(OAc)3, ClCH2-
CH2Cl (31% for 3 steps); (f) 26, K2CO3, cat. NaI, MeCN, ∆ (88%); (g)
(1) Ti(O-i-Pr)4, 2-i-PrMgCl, Et2O, Ϫ50 ЊC to rt, (2) I2, 0 ЊC [56% (78%
t
based on recovered 35)]; (h) (1) BuLi (2.2 eq.), Et2O, Ϫ80 ЊC, then
excess ClCO2Me, Ϫ80 ЊC, (2) excess ClCO2Me, ClCH2CH2Cl, ∆, 2 h
(61%); (i) Jones’ oxidation then CH2N2 (65%); (j) LiHMDS (2.5 eq.),
THF, 0 ЊC then MeOH (80%); (k) NaOH–MeOH, ∆ (70%).
S-Garner aldehyde 24 by Wittig methylenation and oxazolidine
cleavage to give the Boc protected vinylglycinol 31.25 Dess–
Martin oxidation produced a very unstable aldehyde which was
immediately subjected to N-Boc deprotection–acetal formation
to give an amino acetal which was reductively aminated with
benzaldehyde to give 32 in 31% yield over 3 steps. The ee of this
amine was shown to be 93% by comparison with racemic
material using HPLC on a chiral column [Chiralpak AS,
Experimental
i
1:99 PrOH–hexane, Rt 324 s (vs. 287 s)]. Alkylation with allyl
NMR spectra were recorded on JEOL GX-270 or Bruker AMX
400 instruments. Tetramethylsilane (TMS) or CDCl3–CHCl3
was used as the internal standard and J values are in Hz.
Carbon spectra were verified using DEPT experiments. Melting
points were recorded on a Electrothermal IA9100 digital
melting point apparatus and are uncorrected. Infrared (IR)
chloride 26 gave diene 33 in 88% yield.
Ti()-mediated cyclisation–iodination gave, again, the cis,cis-
pyrrolidine 34 as the only cyclised product in 56% yield (78%
based on recovered diene 33). Lithium–halogen exchange and
quenching with excess methyl chloroformate gave 35 in 61%
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Table 2 Related metallabicyclisation studies
Major product(s)
after Hϩ
Zr() Yield (%);
cis:trans
Ti() Yield (%);
cis:trans
Entry no.
i
Starting diene
50
52
10:1
cis only (39)
ii
(No 41
observed)
(No 41
observed)
iii
59
1.0:1.4
58
cis only (43)
iv
(No 46 or 47
observed)
63
cis only
1:1 mixture of
diastereomers
(46 and 47)
spectra were recorded on an ATI Mattson Genesis FT-IR spec-
trometer. Low resolution electron impact (EI) mass spectra
were recorded on a Kratos MS 25 spectrometer. Chemical ion-
isation (CI) and high resolution mass spectra (HRMS) were
recorded on a Micromass Autospec spectrometer. Elemental
analyses were carried out at the University of Newcastle.
Chromatography is medium pressure flash chromatography and
was performed using Matrex silica 60 (70–200) with the eluent
specified. Where necessary, ether and THF were distilled from
sodium–benzophenone ketyl, and DCM from calcium hydride,
immediately before use. Light petroleum is the fraction bp 40–
60 ЊC which was redistilled before use. Except where specified,
all reagents were purchased from commercial sources and were
used without further purification.
mmol) under N2 and stirred for 1 h, followed by addition of
diene 8 (100 mg, 0.49 mmol) in THF (5 mL). The reaction was
allowed to warm up to rt and stirred for a further 2 h. The
reaction was quenched with MeOH (5 mL) and was stirred for a
further 1 h before dilution with Et2O (30 mL). The organic layer
was separated, washed with sat. NaHCO3, dried (MgSO4), fil-
tered and concentrated in vacuo to give the crude product as a
colourless oil. Purification by flash column chromatography
eluting with CH2Cl2–MeOH (9:1) gave the title compound 12 as
an inseparable pair of diastereomers (50 mg, 50%, 1:1) as a
colourless oil; Rf 0.15 (EtOAc); νmax cmϪ1 2957, 2874, 1454;
δH (270 MHz, CDCl3, cis ϩ trans) 0.85–1.10 (6H, 2 × m, CH3),
1.10–2.35 (6H, m, CH3CH2 ϩ 2 × NCH2CH), 2.65–2.80 ϩ
2.95–3.10 (2 × 1H, m, CHCH), 3.51–3.72 (2H, m, NCH2Ph),
7.09–7.34 (5H, m, Ar-H); δC (67.9 MHz, CDCl3, cis ϩ trans)
12.8 ϩ 13.1 (CH3), 14.6 ϩ 19.6 (CH3), 22.4 ϩ 27.4 (CH2),
34.1 ϩ 38.7 (CH), 42.3 ϩ 48.1 (CH), 59.9, 60.4, 60.8, 61.1,
62.3, 62.6 (6 × CH2), 126.7 (CH), 128.1 (CH), 128.8 (CH),
139.4 (C); m/z (EI) 203 (MHϩ, 100%); HRMS (EI) [Mϩ]
C14H21N requires 203.1674. Found 203.1681 (3.6 ppm error).
(2E)-N-Allyl-N-benzylbut-2-en-1-amine 8
To (2E)-N-allylbut-2-en-1-amine28 (100 mg, 0.90 mmol) and
K2CO3 (249 mg, 1.80 mmol) in MeCN (10 mL) was added BnBr
(0.12 mL, 1.00 mmol) and the reaction was stirred overnight
under N2. The solvent was evaporated in vacuo and the residue
was taken up in Et2O (20 mL) and water (20 mL). The organic
layer was separated, dried (Na2SO4), filtered and concentrated
in vacuo to give the crude product as a colourless oil which was
purified by flash column chromatography eluting with light
petroleum–EtOAc (15:1) to afford the title compound 8 (86 mg,
48%) as a colourless oil; Rf 0.40 (light petroleum–EtOAc, 9:1);
νmax cmϪ1 2918, 2791, 1449, 1118, 968, 917, 697; δH (270 MHz,
CDCl3) 1.70 (3H, d, J 6.0, CH3), 3.00–3.15 (4H, m, 2 ×
(2E)-N-Allyl-N-benzyl-4-phenoxybut-2-en-1-amine 9
To N-allyl-N-benzylamine18 (200 mg, 1.36 mmol), K2CO3 (376
mg, 2.72 mmol) and NaI (40 mg, 0.27 mmol) in MeCN (10 mL)
was added [(1E)-3-chloroprop-1-enyloxy]benzene29 (248 mg,
1.36 mmol) and the reaction was refluxed overnight under N2.
The solvent was evaporated and the residue was taken up in
Et2O (20 mL) and water (20 mL). The organic layer was separ-
ated, dried (Na2SO4), filtered and concentrated in vacuo to give
the crude product as a colourless oil which was purified by flash
column chromatography eluting with light petroleum–EtOAc
(9:1) to afford the title compound 9 (300 mg, 75%) as a colour-
less oil; Rf 0.25 (light petroleum–EtOAc, 9:1) (Found: C 81.6,
H 7.8, N 4.8. C20H23NO requires C 81.9, H 7.9, N 4.8%); νmax
cmϪ1 3063, 3027, 2797, 1599, 1495, 1241, 753; δH (270 MHz,
CDCl3) 3.18 (2H, d, J 6.3, NCH2CH), 3.21 (2H, d, J 4.5,
NCH2CH), 3.67 (2H, s, CH2Ph), 4.60–4.66 (2H, d, J 3.9,
CH CH᎐CH), 3.55 (2H, s, CH Ph), 5.10–5.25 (2H, m, CH᎐
᎐
᎐
2
2
CH ), 5.45–5.70 (2H, m, CH᎐CHCH ), 5.85–5.95 (1H, m,
᎐
2
3
CH᎐CH ), 7.15–7.28 (5H, m, Ar-H); δ (67.9 MHz, CDCl3),
᎐
2
C
17.9 (CH3), 55.5 (CH2), 56.3 (CH2), 57.4 (CH2), 117.3 (CH2),
126.7, 127.6, 128.1, 128.3, 128.9 (5 × CH), 136.0 (CH), 139.5
(C); m/z (CI) 202 (MHϩ, 100%); HRMS (CI) [MHϩ] C14H20N
requires 202.1600. Found: 202.1596 (2.1 ppm error).
cis- and trans-1-Benzyl-3-ethyl-4-methylpyrrolidine 12
To zirconocene dichloride (123 mg, 0.42 mmol) in THF (10 mL)
CH OPh), 5.20–5.33 (2H, m, CH᎐CH ), 5.89–6.04 (3H, m,
᎐
2 2
at Ϫ78 ЊC was added n-BuLi (2.5 M in hexanes, 0.34 mL, 0.84
CH᎐CH, CH᎐CH ), 6.97–7.11 (3H, m, Ar-H), 7.29–7.48 (7H,
᎐ ᎐
2
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m, Ar-H); δC (67.9 MHz, CDCl3) 55.0, 56.5, 57.6 (3 × CH2),
68.1 (CH2), 114.8 (CH), 117.5 (CH2), 120.7 (CH), 126.8, 128.0,
128.1, 128.9, 129.4, 131.7, 135.7 (7 × CH), 139.3 (C), 159.5 (C);
m/z (CI) 294 (MHϩ, 100%); HRMS (CI) [MHϩ] C20H24NO
requires 294.1858. Found 294.1860 (0.8 ppm error).
by flash column chromatography eluting with EtOAc–light
petroleum (1:9) to afford the title compounds 13b as an insepar-
able mixture of 2 diastereomers (159 mg, 67%, 6:1); Rf 0.20
(EtOAc–light petroleum, 1:9); νmax cmϪ1 2791, 1494, 1453,
1227, 917; δH (270 MHz, CDCl3, cis) 2.35–3.70 (10H, m,
N(CH2Ph)CH2CH(CH2)CH(CH)CH2), 4.95–5.12 (2H, m,
cis- and trans-1-Benzyl-3-methyl-4-vinylpyrrolidine 13a
CH᎐CH ), 5.65–5.82 (1H, m, CH᎐CH ), 7.21–7.35 (5H, m,
᎐ ᎐
2 2
Ar-H); δC (67.9 MHz, CDCl3, cis) 34.8 (CH2), 43.7 (CH), 45.4
(CH), 59.2 (2 × CH2), 60.0 (CH2), 117.3 (CH2), 127.2 (CH),
128.3 (CH), 128.8 (CH), 136.1 (CH), 138.2 (C); m/z (CI) 280,
282 (MHϩ 100%); HRMS (CI) [MHϩ] C14H19N79Br requires
280.0701. Found 280.0702 (0.3 ppm error).
Zirconium procedure. To zirconocene dichloride (110 mg,
0.38 mmol) in THF (5 mL) at Ϫ78 ЊC was added n-BuLi (1.6 M
in hexanes, 0.47 mL, 0.75 mmol) under N2 and stirred for 1 h
followed by addition of diene 9 (100 mg, 0.34 mmol) in THF
(2 mL). The reaction was allowed to warm up to rt and stirred
for a further 4.5 h. The reaction was quenched with 2 M HCl
(2 mL) and stirred for 10 min followed by dilution with Et2O (30
mL) and 30%NaOH (10 mL). The organic layer was separated,
dried (Na2SO4), filtered and concentrated in vacuo to give the
crude product as a yellow oil which was purified by flash
column chromatography eluting with EtOAc–light petroleum
(1:1) to afford the title compounds 13a as an inseparable mix-
ture of 2 diastereomers (47 mg, 69%, 3:1) as a colourless oil; Rf
0.20 (light petroleum–EtOAc, 3:1); νmax cmϪ1 2957, 2785, 1639,
1454, 910, 735; δH (270 MHz, CDCl3, cis) 0.89 (3H, d, J 7.0,
CH3), 2.01 (1H, apparent t, J 9.1, CH3(CH)CHCH2), 2.18–2.51
(3H, m, CH3(CH)CHCH2), 2.95–3.06 (2H, m, NCH2CH-
(CH)CH), 3.56–3.68 (2H, m, NCH2Ph), 4.90–5.01 (2H, m,
cis- and trans-1-Benzyl-3-(iodomethyl)-4-vinylpyrrolidine 13c
Zirconium procedure. To zirconocene dichloride (120 mg,
0.41 mmol) in THF (5 mL) at Ϫ78 ЊC under N2 was added
n-BuLi (1.6 M in hexanes, 0.51 mL, 0.82 mmol) and the reac-
tion stirred for 1 h followed by addition of diene 9 (100 mg, 0.34
mmol) in THF (2 mL) and allowed to warm slowly to rt. The
reaction was stirred for 1 h then cooled to 0 ЊC and iodine [173
mg in THF (2 mL), 0.68 mmol] was added. The reaction was
stirred for 30 min then quenched with MeOH (2 mL) and
stirred for 2 min followed by dilution with Et2O (50 mL) and
washing with sat. NaHCO3 (20 mL) then 1 M NaOH (10 mL).
The combined aqueous layers were re-extracted with Et2O (30
mL). The combined organic layers were dried (Na2SO4), filtered
and concentrated in vacuo to give the crude product as a colour-
less oil which was purified by flash column chromatography
eluting with EtOAc–light petroleum (1:9→1:4) to afford the
title compounds 13c as an inseparable mixture of 2 diastereom-
ers (90 mg, 81%, 3:1) as a colourless oil, Rf 0.30 (EtOAc–light
petroleum, 1:9); νmax cmϪ1 2786, 1493, 1185, 915, 698; δH (270
MHz, CDCl3, cis) 2.29 (1H, dd, J 9.2, 7.8, CH2I), 2.41 (1H, dd,
J 9.2, 6.3, CH2I), 2.68–3.21 (6H, m, NCH2CH(CH2)CH-
(CH)CH2), 3.64 (2H, apparent d, J 2.8, NCH2Ph), 5.06–5.13
CH᎐CH ), 5.70–5.88 (1H, m, CH᎐CH ), 7.20–7.34 (5H, m,
᎐
᎐
2
2
Ar-H); δH (270 MHz, CDCl3, trans) 1.01 (3H, d, J 6.8, CH3),
1.88–2.02 (1H, m, CH3(CH)CHCH2), 2.18–2.51 (3H, m,
CH3(CH)CHCH2), 2.75–2.82 (2H, m, NCH2CH(CH)CH),
3.56–3.68 (2H, m, NCH Ph), 4.90–5.01 (2H, m, CH᎐CH ),
᎐
2
2
5.70–5.88 (1H, m, CH᎐CH ), 7.20–7.34 (5H, m, Ar-H); δ (67.9
᎐
2
C
MHz, CDCl3, cis) 15.6 (CH3), 35.2 (CH), 45.6 (CH), 59.5,
60.7, 62.2 (3 × CH2), 115.1 (CH2), 126.8, 128.1, 128.8, 138.7
(4 × CH), 139.3 (C); δC (67.9 MHz, CDCl3, trans) 17.9 (CH3),
39.1 (CH), 51.2 (CH), 59.9, 61.7, 60.8 (3 × CH2), 114.1 (CH2),
126.8, 128.1, 128.8, 139.3 (4 × CH), 140.8 (C); m/z (EI) 210
(MHϩ, 30%); HRMS (EI) [Mϩ] C14H19N requires 201.1518.
Found 201.1520 (1.0 ppm error).
(2H, m, CH᎐CH ), 5.68–5.81 (1H, m, CH᎐CH ), 7.21–7.35
᎐
᎐
2
2
(5H, m, Ar-H); δC (67.9 MHz, CDCl3, cis) 8.0 (CH2), 44.3
(CH), 46.0 (CH), 59.6 (CH2), 60.2 (CH2), 61.1 (CH2), 117.2
(CH2), 127.0 (CH), 128.3 (CH), 128.7 (CH), 136.2 (CH), 138.6
(C); m/z (CI) 328 (MHϩ, 100%); HRMS (CI) [MHϩ] C14H19NI
requires 328.0562. Found 328.0569 (2.2 ppm error).
Titanium procedure. To diene 9 (100 mg, 0.34 mmol) in dry
Et2O at Ϫ50 ЊC under N2 and stirred was added Ti(O-i-Pr)4
(126 µL, 0.43 mmol) then i-PrMgCl (2.0 M in Et2O, 0.41 mL,
0.82 mmol) and the reaction was allowed to warm to rt. The
reaction was stirred for 30 min then quenched with MeOH
(2 mL) and stirred for 2 min followed by dilution with Et2O (50
mL) and washing with sat. NaHCO3 (20 mL) then 1 M NaOH
(10 mL). The combined aqueous layers were re-extracted with
Et2O (30 mL). The combined organic layers were dried
(Na2SO4), filtered and concentrated in vacuo to give the crude
product as a colourless oil which was purified by flash column
chromatography eluting with EtOAc–light petroleum (1:9) to
afford the title compounds 13a as an inseparable mixture of
2 diastereomers (65 mg, 95%, 6:1) as a colourless oil. The
spectroscopic data matched those reported above.
Titanium procedure. To diene 9 (400 mg, 1.36 mmol) in dry
Et2O (8 mL) at Ϫ50 ЊC under N2 was added Ti(O-i-Pr)4 (0.50
mL, 1.72 mmol) then i-PrMgCl (2.0 M in Et2O, 1.64 mL, 3.28
mmol) and allowed to warm slowly to rt. The reaction was
stirred for 1 h then cooled to 0 ЊC and iodine [1.035 g in Et2O
(4 mL), 2.55 mmol] was added. The reaction was stirred for 30
min then quenched with MeOH (2 mL) and stirred for 2 min
followed by dilution with Et2O (50 mL) and washing with sat.
NaHCO3 (20 mL) then 1 M NaOH (10 mL). The combined
aqueous layers were re-extracted with Et2O (30 mL). The com-
bined organic layers were dried (Na2SO4), filtered and concen-
trated in vacuo to give the crude product as a colourless oil
which was purified by flash column chromatography eluting
with EtOAc–light petroleum (1:9) to afford the title compounds
13c as an inseparable mixture of 2 diastereomers (320 mg, 72%,
6:1); the spectroscopic data matched those reported above.
cis- and trans-1-Benzyl-3-(bromomethyl)-4-vinylpyrrolidine 13b
Titanium procedure. To diene 9 (250 mg, 0.85 mmol) in dry
Et2O (8 mL) at Ϫ50 ЊC under N2 was added Ti(O-i-Pr)4 (315
µL, 1.08 mmol) then i-PrMgCl (2.0 M in Et2O, 1.03 mL, 1.06
mmol) and stirred at that temperature for 10 min before being
allowed to warm slowly to rt. The reaction was stirred for 1 h
then cooled to 0 ЊC and bromine [408 mg in Et2O (4 mL), 2.55
mmol] was added. The reaction was stirred for 30 min then
quenched with MeOH (2 mL) and stirred for 2 min followed by
dilution with Et2O (50 mL) and washing with sat. NaHCO3 (20
mL) then 1 M NaOH (10 mL). The combined aqueous layers
were re-extracted with Et2O (30 mL). The combined organic
layers were dried (Na2SO4), filtered and concentrated in vacuo
to give the crude product as a colourless oil which was purified
cis- and trans-1-Benzyl-4-vinylpyrrolidin-3-ylacetaldehyde 13d
Zirconium procedure. To zirconocene dichloride (120 mg,
0.41 mmol) in THF (5 mL) at Ϫ78 ЊC was added n-BuLi (1.6 M
in hexanes, 0.51 mL, 0.82 mmol) under N2 and stirred for 1 h
followed by addition of diene 9 (100 mg, 0.34 mmol) in THF
(2 mL). The reaction was allowed to warm up to rt and stirred
for a further 1 h. n-BuNC (40 mg, 0.38 mmol) was added at 0 ЊC
and the reaction was heated to 45 ЊC for 3 h followed by
quenching with 50% AcOH (2 mL) at Ϫ78 ЊC to rt and stirring
for 10 min. 30% NaOH (5 mL) was added along with Et2O
J. Chem. Soc., Perkin Trans. 1, 2000, 3194–3204
3199

View Article Online
(20 mL) and the organic layer was separated, dried (Na2SO4),
filtered and concentrated in vacuo to give the crude product as
a yellow oil which was purified by flash column chromato-
graphy eluting with EtOAc to afford the title compounds 13d as
an inseparable mixture of 2 diastereomers (36 mg, 47%, 3:1) as
a colourless oil, Rf 0.10 (light petroleum–EtOAc, 1:1); νmax
cmϪ1 2923, 1721, 1640, 1029, 734; δH (270 MHz, CDCl3, cis)
2.11 (1H, dd, J 9.0, 7.5, CH2CHO), 2.24–2.56, 2.70–2.95
(4H ϩ 3H, 2 × m, NCH2CH(CH2)CH(CH)CH2), 3.56 (2H, s,
cation by flash column chromatography eluting with EtOAc–
light petroleum (1:1) afforded the title compound 14 (60 mg,
85%) as a colourless oil, Rf 0.25 (light petroleum–EtOAc, 3:1);
νmax cmϪ1 2960, 2917, 2787, 1646, 1453, 887, 698; δH (270 MHz,
CDCl3) 0.81 (3H, d, J 7.0, CHCH3), 1.72 (3H, s, CH3CR2), 2.08
(1H, dd, J 9.2, 5.6, CH2CHCH3), 2.38–2.58 (2H, m, CHCH),
2.76–2.87 (2H, m, CH2CH(CR2)CH), 3.13 (1H, dd, J 9.2, 7.3,
CH CHCH ), 3.64 (2H, s, NCH Ph), 4.66 (1H, br s, CR ᎐CH ),
᎐
2
3
2
2
2
5.00 (1H, br s, CR ᎐CH ), 7.21–7.35 (5H, m, Ar-H); δ (67.9
᎐
2
2
C
NCH Ph), 4.90–4.97 (2H, m, CH᎐CH ), 5.62–5.72 (1H, m,
MHz, CDCl3) 15.9 (CH3), 23.6 (CH3), 33.8 (CH), 48.2 (CH),
56.1, 61.1, 62.4 (3 × CH2), 110.8 (CH2), 126.8 (CH), 128.2
(CH), 128.7 (CH), 139.5 (C), 144.3 (C); m/z (CI) 216 (MHϩ,
100%); HRMS (CI) [MHϩ] C15H22N requires 216.1752. Found:
216.1747 (2.6 ppm error).
᎐
2
2
CH᎐CH ), 7.14–7.24 (5H, m, Ar-H), 9.65 (1H, s, CHO); δ
᎐
2
C
(67.9 MHz, CDCl3, cis) 35.5 (CH), 44.6 (CH), 45.1 (CH2), 59.1,
59.1, 60.3 (3 × CH2), 116.7 (CH2), 127.2, 128.3, 128.8, 128.9
(4 × CH), 137.9 (C), 201.8 (C); δC (67.9 MHz, CDCl3, trans)
38.4 (CH), 48.1 (CH), 49.0 (CH2), 59.1, 59.2, 60.1 (3 × CH2),
115.7 (CH2), 127.1, 128.8, 138.5 (4 × CH), 139.3 (C), 201.6 (C);
m/z (CI) 230 (MHϩ, 25%); HRMS (CI) [MHϩ] C15H20NO
requires 230.1545. Found: 230.1540 (2.1 ppm error).
(2Z)-N-Benzyl-3-methyl-N-(1-methylprop-2-enyl)-4-phenoxy-
but-2-en-1-amine 15
(a) To benzylamine (500 mg, 4.66 mmol), K2CO3 (612 mg, 4.43
mmol) and NaI (66 mg, 0.44 mmol) in MeCN (10 mL) was
added 3-chlorobut-1-ene (401 mg, 4.43 mmol) and the reaction
was refluxed overnight under N2. The solvent was evaporated
and the residue was taken up in Et2O (40 mL) and sat. NaHCO3
(20 mL). The organic layer was separated, dried (Na2SO4),
filtered and concentrated in vacuo to give the crude product
as a colourless oil which was purified by flash column
chromatography eluting with CH2Cl2–MeOH (9:1) to afford
N-benzyl-N-(1-methylprop-2-enyl)amine (100 mg, 14%) as a
colourless oil; Rf 0.35 (CH2Cl2–MeOH, 9:1) which was fully
characterised.
(b) To N-benzyl-N-(1-methylprop-2-enyl)amine (95 mg, 0.59
mmol), K2CO3 (192 mg, 1.18 mmol) and NaI (18 mg, 0.12
mmol) in MeCN (20 mL) was added allyl chloride 26 (116 mg,
0.59 mmol) and the reaction was refluxed overnight under N2.
Work-up as for amine 9 followed by purification by flash
column chromatography eluting with light petroleum–EtOAc
(20:1) afforded the title compound 15 (150 mg, 79%) as a col-
ourless oil; Rf 0.55 (light petroleum–EtOAc, 9:1); νmax cmϪ1
2970, 1598, 1495, 1238, 1008; δH (270 MHz, CDCl3) 1.14 (3H,
(2E)-N-Allyl-N-benzyl-3-methyl-4-phenoxybut-2-en-1-amine
10
To N-allyl-N-benzylamine18 (251 mg, 1.71 mmol), K2CO3 (394
mg, 2.85 mmol) and NaI (43 mg, 0.28 mmol) in MeCN (10 mL)
was added {[(2E)-4-chloro-2-methylbut-2-enyl]oxy}benzene
(280 mg, 1.42 mmol) and the reaction was refluxed overnight
under N2. Work-up as for amine 9 followed by purification by
flash column chromatography eluting with light petroleum–
EtOAc (9:1) afforded the title compound 10 (354 mg, 81%) as a
colourless oil; Rf 0.20 (light petroleum–EtOAc, 9:1); νmax cmϪ1
2919, 2802, 1598, 1494, 1241, 735, 692; δH (270 MHz, CDCl3)
1.70 (3H, s, CH3), 3.05 (2H, d, J 6.3, NCH2CH), 3.11 (2H, d,
J 6.5, NCH2CH), 3.54 (2H, s, NCH2Ph), 4.41 (2H, s, CH2OPh),
5.11–5.20 (2H, m, CH᎐CH ), 5.69 (1H, t, J 6.5, CH CH᎐CR ),
᎐
᎐
2
2
2
5.81–5.95 (1H, m, CH᎐CH ), 6.90–6.94 (3H, m, Ar-H), 7.23–
᎐
2
7.31 (7H, m, Ar-H); δC (67.9 MHz, CDCl3) 14.1 (CH3), 50.5,
56.7, 57.8 (3 × CH2), 73.4 (CH2), 114.9 (CH), 117.4 (CH2),
120.7 (CH), 125.8, 126.8, 128.1, 128.9, 129.3, 135.9 (6 × CH),
133.8 (C) 139.3 (C), 158.7 (C); m/z (CI) 308 (MHϩ, 100%);
HRMS (CI) [MHϩ] C21H26NO requires 308.2014. Found:
308.2014 (0.1 ppm error).
d, J 6.8, CH CH), 1.82 (3H, s, CH CR᎐CH), 3.12 (2H, m,
᎐
3
3
NCH2CH), 3.37 (1H, apparent quintet, J 6.8, NCH), 3.55 (1H,
d, J 13.8, NCH2Ph), 3.61 (1H, d, J 13.8, NCH2Ph), 4.42 (2H, s,
CH OPh), 5.04–5.15 (2H, m, CH᎐CH ), 5.51 (1H, apparent t,
᎐
2
2
(2Z)-N-Allyl-N-benzyl-3-methyl-4-phenoxybut-2-en-1-amine
11
J 5.9, CH᎐CR ), 5.90 (1H, ddd, J 17.2, 10.5, 6.8, CH᎐CH ),
᎐
᎐
2
2
6.84–6.96 (3H, m, Ar-H), 7.16–7.36 (7H, m, Ar-H); δC (67.9
MHz, CDCl3) 15.3 (CH3), 21.5 (CH3), 46.7 (CH2), 53.6 (CH2),
56.2 (CH), 66.7 (CH2), 114.6 (CH), 115.5 (CH2), 120.7 (CH),
126.6, 128.1, 128.5, 139.4, 140.2, 140.6 (9 × CH), 158.9 (C); m/z
(CI) 322 (MHϩ, 100%); HRMS (CI) [MHϩ] C22H28NO requires
322.2171. Found 322.2183 (3.7 ppm error).
To N-allyl-N-benzylamine18 (90 mg, 0.61 mmol), K2CO3 (141
mg, 1.02 mmol) and NaI (15 mg, 0.10 mmol) in MeCN (10 mL)
was added allyl chloride 26 (100 mg, 0.51 mmol) and the reac-
tion was stirred overnight under N2. Work-up as for amine
9 followed by purification by flash column chromatography
eluting with light petroleum–EtOAc (7:1) afforded the title
compound 11 (140 mg, 89%) as a colourless oil; Rf 0.20 (light
petroleum–EtOAc, 9:1); νmax cmϪ1 2918, 2801, 1598, 1495,
1239, 1008, 753, 693; δH (270 MHz, CDCl3) 1.86 (3H, d, J 1.0,
CH3), 3.06–3.12 (4H, m, 2 × NCH2CH), 3.56 (2H, s, NCH2Ph),
2,3-trans-3,4-cis-1-Benzyl-4-isopropenyl-2,3-dimethylpyrrolidine
and 2,3-cis-3,4-cis-1-benzyl-4-isopropenyl-2,3-dimethylpyrrol-
idine 16 and 17
Titanium procedure. Diene 15 (75 mg, 0.23 mmol) was treated
with Ti(O-i-Pr)4 and i-PrMgCl according to the general
procedure outlined for the cyclisation of diene 9. Purification
by flash column chromatography eluting with EtOAc–light
petroleum (1:1) afforded the title compounds 16 and 17 as an
inseparable mixture of 2 diastereomers (39 mg, 74%, 1:4) as
colourless oils; Rf 0.20 (EtOAc–light petroleum, 1:1); νmax cmϪ1
2965, 1646, 1453, 1376, 697; δH (270 MHz, CDCl3) 0.75 (3H, d,
J 6.3, NCH(CH3)CH(CH3)), 1.08 (3H, d, J 6.3, NCH(CH3)-
4.44 (2H, s, CH OPh), 5.11–5.22 (2H, m, CH᎐CH ), 5.57 (1H,
᎐
2
2
dt, J 7.8, 1.0, CH CH᎐CR ), 5.88 (1H, ddt, J 17.2, 10.2, 6.3,
᎐
2
2
CH᎐CH ), 6.85–6.97 (3H, m, Ar-H), 7.21–7.34 (7H, m, Ar-H);
᎐
2
δC (67.9 MHz, CDCl3) 21.5 (CH3), 50.3 (CH2), 56.7 (CH2), 57.8
(CH2), 66.6 (CH2), 114.7 (CH), 117.5 (CH2), 120.7 (CH), 126.8,
128.2, 128.9, 129.4, 135.9 (6 × CH), 134.6 (C), 139.3 (C), 158.9
ϩ
(C); m/z (CI) 308 (MHϩ, 100%); HRMS (CI) [MNH4
]
C21H26NO requires 308.2014. Found 308.2008 (2.0 ppm error).
CH(CH )), 1.70 (3H, s, CH CR᎐CH ), 2.17 (1H, apparent
᎐
3
3
2
cis-1-Benzyl-3-isopropenyl-4-methylpyrrolidine 14
quintet, J 6.3, NCH(CH3)CH(CH3)), 2.44 (1H, dd, J 10.0, 8.7,
NCH2CH), 2.67 (1H, ddd, J 9.5, 8.7, 6.3, NCH2CH), 2.90 (1H,
apparent quintet, J 6.3, NCH), 3.13 (1H, dd, J 10.0, 9.5,
NCH2CH), 3.36 (1H, d, J 13.8, NCH2Ph), 3.97 (1H, d, J 13.8,
Titanium procedure. To diene 11 (100 mg, 0.33 mmol) in dry
Et2O at Ϫ50 ЊC under N2 was added Ti(O-i-Pr)4 (118 µL, 0.39
mmol) then i-PrMgCl (2.0 M in Et2O, 0.39 mL, 0.78 mmol) and
allowed to warm to rt. The reaction was stirred for 30 min then
worked-up as for the preparation of pyrrolidines 13a. Purifi-
NCH Ph), 4.58 (1H, br s, CH CR᎐CH ), 4.79 (1H, br s,
᎐
2
3
2
CH CR᎐CH ), 7.19–7.37 (5H, m, Ar-H); δ (67.9 MHz,
᎐
3
2
C
3200
J. Chem. Soc., Perkin Trans. 1, 2000, 3194–3204

View Article Online
CDCl3) 9.0 (CH3), 15.5 (CH3), 23.1 (CH3), 39.6 (CH), 47.3
(CH), 53.4 (CH2), 58.5 (CH2), 63.2 (CH), 110.4 (CH2), 128.2
(CH), 128.8 (CH), 129.5 (CH), 144.0 (C), 156.2 (C); m/z (CI)
230 (MHϩ, 100%); HRMS (CI) [MHϩ] C16H24N requires
230.1909. Found 230.1912 (1.5 ppm error).
mg, 4.45 mmol), benzaldehyde (520 mg, 4.90 mmol), triethyl-
amine (540 mg, 5.34 mmol) and Na2SO4 (3 g) in CH2Cl2 (25
mL) were heated under reflux overnight under N2. The reaction
was then cooled, filtered and concentrated in vacuo, taken up in
MeOH (20 mL), cooled to 0 ЊC followed by addition of NaBH4
(242 mg, 4.45 mmol). The reaction was warmed to rt and stirred
for a further 1 h. The solvent was then evaporated and the
residue was taken up in EtOAc (60 mL) and sat. NaHCO3 (40
mL). The organic layer was separated, dried (Na2SO4), filtered
and concentrated in vacuo to give the crude product which was
dissolved in DMF (10 mL) along with TBSCl (810 mg, 5.37
mmol), imidazole (664 mg, 9.75 mmol) and was stirred over-
night under N2. The solvent was then evaporated in vacuo and
the residue was taken up in EtOAc (60 mL) and sat. NaHCO3
(20 mL). The organic layer was separated, dried (Na2SO4), fil-
tered and concentrated in vacuo to give the crude product as a
colourless oil which was purified by flash column chromato-
graphy eluting with light petroleum–EtOAc (9:1) to afford
(2R)-N-benzyl-1-tert-butyl(dimethyl)silyloxybut-3-en-2-amine
(900 mg, 70%) as a colourless oil; Rf 0.35 (light petroleum–
EtOAc, 9:1); [α]D Ϫ26.6 (c 0.98, CHCl3) which was fully
characterised.
(b) To (2R)-N-benzyl-1-tert-butyl(dimethyl)silyloxybut-3-en-
2-amine (449 mg, 1.54 mmol), K2CO3 (426 mg, 3.08 mmol) and
NaI (46 mg, 0.30 mmol) in MeCN (30 mL) was added allyl
chloride 26 (303 mg, 1.54 mmol) and the reaction was refluxed
overnight under N2. Standard work up as for amine 9 followed
by purification by flash column chromatography eluting with
light petroleum–EtOAc (30:1) afforded the title compound 27
(594 mg, 86%) as a colourless oil; Rf 0.50 (light petroleum–
EtOAc, 9:1); [α]D ϩ1.8 (c 0.95, CHCl3) (Found: C 74.5, H 9.2,
N, 3.5. C28H41NO2Si requires C 74.45, H 9.15, N 3.1%); νmax
cmϪ1 2928, 2856, 1598, 1495, 1239, 1102, 837, 753; δH (270
MHz, CDCl3) 0.05 (6H, m, OSi(CH3)2C(CH3)3), 0.91 (9H, s,
{[(2Z)-4-Chloro-2-methylbut-2-enyl]oxy}benzene 26
(a) To diethyl phosphonoacetate (25.85 g, 123 mmol) in THF
(250 mL) was added NaH (60%, 4.92 g, 123 mmol) portionwise
under N2 and stirring was continued for 30 min. The reaction
mixture was cooled to Ϫ15 ЊC and 1-phenoxyacetone (15.79 g,
17.2 mL, 105 mmol) was added dropwise over 20 min and
stirred at Ϫ15 ЊC for a further 30 min. The reaction was
quenched with water (150 mL) and diluted with Et2O (200 mL)
and the organic layer was separated and washed with sat.
NaHCO3 (100 mL) then 2 M HCl (100 mL). The organic layer
was dried (Na2SO4), filtered and concentrated in vacuo to give
the crude product as a colourless oil which was purified by flash
column chromatography eluting with light petroleum–EtOAc
(20:1) to afford methyl (2Z)-3-methyl-4-phenoxyybut-2-enoate
(6.92 g, 32%) as a colourless oil, Rf 0.25 (light petroleum–
EtOAc, 20:1) followed by methyl (2E)-3-methyl-4-phenoxybut-
2-enoate (13.44 g, 62%) as a colourless oil; Rf 0.10 (light
petroleum–EtOAc, 20:1) which were fully characterised.
(b) To the Z-α,β-unsaturated ester above (1.00 g, 4.85 mmol)
in dry toluene (20 mL) at Ϫ78 ЊC was added DIBAL (1.0 M in
toluene, 9.70 mL, 9.70 mmol) and the reaction was stirred for
30 min under N2. The reaction was quenched by addition of
MeOH (10 mL) and allowed to warm to rt. 10% Citric acid (50
mL) and Et2O (50 mL) were added and the reaction stirred
vigorously for 1 h. The organic layer was separated, dried
(Na2SO4), filtered and concentrated in vacuo to give the crude
product as a colourless oil which was used without purification
in the next reaction.
OSi(CH ) C(CH ) ), 1.86 (3H, d, J 1.0, CH CR᎐CH), 3.14–3.35
᎐
3
2
3
3
3
(c) To the crude alcohol in CH2Cl2 (100 mL) was added
DMAP (1.19 g, 9.70 mmol) then tosyl chloride (1.11 g, 5.81
mmol) followed by stirring overnight. The organic layer was
then washed with sat. NaHCO3 (30 mL) and dried (Na2SO4),
filtered and concentrated in vacuo to give the crude product as a
thick yellow gum which was purified by flash column chromato-
graphy (pre-adsorbed onto silica) eluting with light petroleum–
EtOAc (30:1) to afford the title compound 26 (372 mg, 39%) as
a colourless oil; Rf 0.40 (light petroleum–EtOAc, 9:1); νmax
cmϪ1 2947, 1598, 1495, 1238, 1008, 754, 691; δH (270 MHz,
CDCl3) 1.90 (3H, t, J 0.7, CH3), 4.15 (2H, J 8.0, CH2Cl), 4.55
(3H, m, NCH2CH, NCH), 3.54 (1H, d, J 14.0, NCH2Ph), 3.72–
3.86 (2H, m, OCH2SiR3), 3.85 (1H, d, J 14.0, NCH2Ph), 4.45
(2H, s, CH OPh), 5.17–5.29 (2H, m, CH᎐CH ), 5.54 (1H, t,
᎐
2
2
J 6.0, CR ᎐CH), 5.85 (1H, ddd, J 17.2, 9.7, 6.8, CH᎐CH ),
᎐
᎐
2
2
6.87–6.99 (3H, m, Ar-H), 7.23–7.40 (7H, m, Ar-H); δC (67.9
MHz, CDCl3) Ϫ5.4 (CH3), Ϫ5.4 (CH3), 18.3 (C), 21.4 (CH3),
25.9 (CH3), 47.6 (CH2), 54.7 (CH2), 63.2 (CH), 64.7 (CH2), 66.9
(CH2), 114.6 (CH), 118.1 (CH2), 120.7 (CH), 126.6 (CH), 128.1
(CH), 128.4 (CH2), 128.5 (CH), 129.5 (CH), 133.8 (C), 135.4
(CH), 140.7 (C), 158.9 (C); m/z (CI) 452 (MHϩ, 100%).
(2H, s, CH OPh), 5.61–5.71 (1H, m, CH᎐CR ), 6.89–7.00 (3H,
᎐
2
2
(2R,3S,4S)-1-Benzyl-2-[tert-butyl(dimethyl)silyloxy-methyl]-3-
(iodomethyl)-4-isopropenylpyrrolidine 28
m, Ar-H), 7.23–7.33 (2H, m, Ar-H); δC (67.9 MHz, CDCl3)
21.4 (CH3), 39.7 (CH2), 66.1 (CH2), 114.6 (CH), 121.1 (CH),
124.6 (CH), 129.5 (CH), 137.7 (C), 158.5 (C); m/z (CI) 214
(MNH4ϩ, 100%); HRMS (CI) [MNH4ϩ] C11H17NOCl requires
214.0999. Found 214.0993 (2.5 ppm error).
To diene 27 (197 mg, 0.44 mmol) in dry Et2O (8 mL) at Ϫ50 ЊC
under N2 was added Ti(O-i-Pr)4 (164 µL, 0.55 mmol) then
i-PrMgCl (2.0 M in Et2O, 0.53 mL, 1.06 mmol) and stirred at
that temperature for 10 min before being allowed to warm
slowly to rt. The reaction was stirred for 1 h then cooled to 0 ЊC
and iodine [335 mg in Et2O (4 mL), 1.32 mmol] was added. The
reaction was stirred for 30 min then quenched with MeOH
(2 mL) and stirred for 2 min followed by dilution with Et2O (50
mL) and washing with sat. NaHCO3 (20 mL) then 1 M NaOH
(10 mL). The combined aqueous layers were re-extracted
with Et2O (30 mL). The combined organic layers were dried
(Na2SO4), filtered and concentrated in vacuo to give the crude
product as a colourless oil which was purified by flash column
chromatography eluting with EtOAc–light petroleum (1:25) to
afford the title compound 28 (148 mg, 70%) as a pale yellow oil;
Rf 0.25 (EtOAc–light petroleum, 1:9); [α]D ϩ40.6 (c 0.32,
CHCl3); νmax cmϪ1 2928, 1470, 1255, 1987, 836; δH (270 MHz,
CDCl3) 0.09 (3H, s, OSi(CH3)2C(CH3)3), 0.09 (3H, s, OSi-
(CH3)2C(CH3)3), 0.92 (9H, s, OSi(CH3)2C(CH3)3), 1.86 (3H, s,
{[(2E)-4-Chloro-2-methylbut-2-enyl]oxy}benzene E-26
A similar sequence was employed to convert methyl (2E)-3-
methyl-4-phenoxybut-2-enoate into E-26: colourless oil (24%
over 3 steps); Rf 0.55 (light petroleum–EtOAc, 9:1); νmax cmϪ1
2922, 1598, 1495, 1245, 1172, 754; δH (270 MHz, CDCl3)
1.76 (3H, t, J 0.5, CH3), 4.08 (2H, J 7.8, CH2Cl), 4.36 (2H, s,
CH OPh), 5.74 (1H, m, CH᎐CR ), 6.82–6.92 (3H, m, Ar-H),
᎐
2
2
7.15–7.24 (2H, m, Ar-H); δC (67.9 MHz, CDCl3) 13.7 (CH3),
39.9 (CH2), 72.3 (CH2), 114.7 (CH), 120.1 (CH), 122.8 (CH),
129.4 (CH), 137.4 (C), 158.9 (C); m/z (CI) 214 (MNH4ϩ, 100%);
HRMS (CI) [MNH4ϩ] C11H17NOCl requires 214.0999. Found
214.0995 (1.6 ppm error).
N-Benzyl-N-[(1R)-1-(tert-butyl(dimethyl)silyloxymethyl)prop-2-
enyl]-N-[(2Z)-3-methyl-4-phenoxybut-2-enyl]amine 27
(a) (2R)-1-Hydroxybut-3-en-2-amine hydrochloride21a 25 (550
CH CR᎐CH ), 2.45 (1H, dd, J 9.7, 7.3, CH I), 2.76–3.13 (5H,
᎐
3
2
2
m, CHCH2I, NCH2CH), 3.42–3.50 (2H, m, NCH, NCH2Ph),
J. Chem. Soc., Perkin Trans. 1, 2000, 3194–3204 3201

View Article Online
3.74 (1H, dd, J 10.7, 7.3, OCH2), 3.94 (1H, dd, J 10.7, 6.5,
OCH2), 4.17 (1H, d, J 13.6, NCH2Ph), 4.90 (1H, br s, CH3-
ated and the product triturated with Et2O (20 mL). The
solution was filtered and then washed with sat. Na2S2O3.
The organic layer was separated, dried (Na2SO4), filtered and
concentrated in vacuo to give the crude aldehyde product as a
colourless oil which was used without purification.
(b) HCl–MeOH was prepared by adding AcCl (4 mL) to
MeOH (24 mL) at 0 ЊC and stirring for 10 min under N2. The
crude aldehyde from (a) was added and the reaction stirred for
2 h. The solvent was evaporated and the amine was purified by
flash column chromatography eluting with CH2Cl2–MeOH–
AcOH–H2O (60:15:2:3) to give (2R)-1,1-dimethoxybut-3-en-
2-amine (200 mg) as a yellow oil, Rf 0.25 (CH2Cl2–MeOH–
AcOH–H2O, 60:15:2:3) which gave consistent NMR data but
was used without further characterisation.
CR᎐CH ), 4.95 (1H, br s, CH CR᎐CH ), 7.25–7.34 (5H, m,
᎐
᎐
2
3
2
Ar-H); δC (67.9 MHz, CDCl3) Ϫ5.4 (CH3), Ϫ5.4 (CH3), 1.7
(CH2I), 18.2 (C), 23.7 (CH3), 26.0 (CH3), 47.5 (CH), 48.0 (CH),
55.6 (CH2), 59.9 (CH2), 63.3 (CH2), 68.7 (CH), 113.7 (CH2),
126.7 (CH), 128.1 (CH), 128.4 (CH), 140.1 (C), 143.4 (C);
m/z (CI) 486 (MHϩ, 100%); HRMS (CI) [MHϩ] C22H37NOSiI
requires 486.1689. Found 486.1697 (1.6 ppm error).
Methyl [(2R,3S,4S)-1-benzyl-2-[tert-butyl(dimethyl)silyloxy-
methyl]-4-isopropenyl-3-(2-methoxy-2-oxoethyl)pyrrolidine-1-
carboxylate 29
To alkyl halide 28 (82 mg, 0.169 mmol) in Et2O (5 mL) at
Ϫ80 ЊC was added t-BuLi (1.7 M in pentane, 0.22 mL, 0.372
mmol) and the reaction was stirred for 3 min under N2. Methyl
chloroformate (0.2 mL, 2.54 mmol) was added and the reaction
was allowed to warm to rt and the reaction stirred for a further
2 h. Methyl chloroformate (0.2 mL, 2.54 mmol) was added
again and the reaction was stirred for 4 h. Methyl chloro-
formate (0.4 mL, 5.08 mmol) was added again and the reaction
was refluxed overnight. The reaction was quenched with tri-
ethylamine (2 mL) then sat. NaHCO3 (20 mL) and then diluted
with Et2O (30 mL). The organic layer was separated, dried
(Na2SO4), filtered and concentrated in vacuo to give the crude
product as a colourless oil which was purified by flash column
chromatography eluting with light petroleum–EtOAc (6:1) to
afford the title compound 29 (46 mg, 71%) as a colourless oil; Rf
0.20 (light petroleum–EtOAc, 6:1); [α]D ϩ39.7 (c 2.00, CHCl3);
νmax cmϪ1 2953, 1740, 1709, 1449, 1379, 838; δH (270 MHz,
d8-toluene, 80 ЊC) 0.01 (3H, s, OSi(CH3)2C(CH3)3), 0.02 (3H, s,
OSi(CH3)2C(CH3)3), 0.87 (9H, s, OSi(CH3)2C(CH3)3), 1.51
(c) To (2R)-1,1-dimethoxybut-3-en-2-amine (248 mg, 1.89
mmol) and PhCHO (201 mg, 1.89 mmol) in 1,2-dichloroethane
(15 mL) was added NaBH(OAc)3 (561 mg, 2.65 mmol) and the
reaction was stirred for 2 h under N2. The solvent was evapor-
ated in vacuo and the residue was taken up in EtOAc (40 mL)
and sat. NaHCO3 (20 mL). The aqueous layer was washed
again with EtOAc (40 mL) and the combined organic layers
were dried (Na2SO4), filtered and concentrated in vacuo to give
the crude product as a colourless oil which was purified by flash
column chromatography eluting with EtOAc to afford the title
compound 32 (184 mg, 31% over 3 steps) as a colourless oil; Rf
0.40 (EtOAc) (93% ee by chiral HPLC—see text for details); [α]D
Ϫ13.1 (c 0.97, CHCl3) (Found: C 70.3, H 8.6, N 6.3. C13H19NO2
requires C 70.6, H 8.65, N 6.3%); νmax cmϪ1 2832, 1454, 1117,
1064; δH (270 MHz, CDCl3) 2.22–2.62 (1H, br, NH), 3.34 (1H,
dd, J 8.3, 6.1, NHCH), 3.45 (3H, s, OCH3), 3.47 (3H, s, OCH3),
3.72 (1H, d, J 13.3, NCH2Ph), 3.98 (1H, d, J 13.3, NCH2Ph),
4.39 (1H, d, J 6.1, CH(OCH3)2), 5.37 (1H, dd, J 17.2, 1.7,
CH᎐CH ), 5.42 (1H, d, J 10.4, 1.7, CH᎐CH ), 5.85 (1H, ddd,
᎐
᎐
2
2
(3H, s, CH CR᎐CH ), 2.08 (1H, dd, J 17.0, 7.1, CH CO Me),
᎐
3
2
2
2
J 17.2, 10.4, 8.3, CH᎐CH ), 7.34–7.43 (5H, m, Ar-H); δ (67.9
᎐
2
C
2.20–2.27 (1H, m, CHCH2CO2Me), 2.61 (1H, dd, J 17.0, 7.0,
CH2CO2Me), 2.96 (1H, m, NCH2CH), 3.12 (1H, apparent t,
J 10.4, NCH2), 3.35 (3H, s, NCO2CH3), 3.43–3.52 (4H, m,
NCH2, CO2CH3), 3.77 (2H, apparent d, J 5.6, OCH2), 4.10–
MHz, CDCl3) 51.2 (CH2), 54.9 (CH3), 55.4 (CH3), 62.7 (CH),
106.8 (CH), 119.3 (CH2), 127.3 (CH), 128.7 (CH), 128.9 (CH),
136.5 (CH), 140.7 (C); m/z (CI) 222 (MHϩ, 100%); HRMS (CI)
[MHϩ] C13H20NO2 requires 222.1494. Found 222.1491 (1.5 ppm
error).
4.20 (1H, m, NCH), 4.49 (1H, br s, CH CR᎐CH ), 4.69 (1H, br
᎐
3
2
s, CH CR᎐CH ); δ (67.9 MHz, d -toluene, 80 ЊC) Ϫ4.4 (CH ),
᎐
3
2
C
8
3
19.4 (C), 24.0 (CH3), 27.1 (CH3), 30.7 (CH2), 40.2 (CH), 48.7
(CH), 50.4 (CH2), 51.8 (CH3), 52.7 (CH3), 62.6 (CH2), 63.8
(CH), 113.4 (CH2), 143.8 (C), 156.7 (C), 173.9 (C); m/z (CI)
386 (MHϩ, 100%); HRMS (CI) [MHϩ] C19H36NO5Si requires
386.2363. Found 386.2377 (3.8 ppm error).
N-Benzyl-N-[(1R)-1-(dimethoxymethyl)prop-2-enyl]-N-[(2Z)-3-
methyl-4-phenoxybut-2-enyl]amine 33
To amine 32 (286 mg, 1.36 mmol), K2CO3 (188 mg, 1.36 mmol)
and NaI (20 mg, 0.13 mmol) in MeCN (30 mL) was added allyl
chloride 26 (268 mg, 1.36 mmol) and the reaction was refluxed
for 3 h under N2. Work-up as for amine 9 followed by purifi-
cation by flash column chromatography eluting with light
petroleum–EtOAc (9:1) afforded the title compound 33 (436
mg, 88%) as a colourless oil; Rf 0.25 (light petroleum–EtOAc,
9:1); [α]D ϩ20.1 (c 0.98, CHCl3) (Found: C 75.6, H 8.1, N, 3.5.
C24H31NO3 requires C 75.6, H 8.2, N 3.7%); νmax cmϪ1 2932,
1598, 1495, 1239, 1060, 753; δH (270 MHz, CDCl3) 1.86 (3H, s,
Methyl (3S,3aS,7aR)-3-isopropenyl-5-oxooctahydropyrano-
[3,4-b]pyrrole-1-carboxylate 30
To ester 29 (39 mg, 0.101 mmol) dissolved in MeOH (6 mL) was
added TsOHؒH2O (2 mg, 0.01 mmol) and the reaction was
stirred for 5 h under N2. The solvent was evaporated and the
residue was taken up in EtOAc (20 mL) and sat. NaHCO3 (10
mL). The organic layer was separated, dried (Na2SO4), filtered
and concentrated in vacuo to give the title compound 30 (24 mg,
100%) as a colourless oil; Rf 0.20 (light petroleum–EtOAc, 2:1);
[α]D ϩ32.1 (c 1.20, CHCl3); νmax cmϪ1 2956, 1748, 1703, 1453,
CH CR᎐CH), 3.07 (1H, dd, J 10.5, 7.8, NCH CH), 3.24–3.38
᎐
3
2
(3H, m, NCH2Ph, NCH2CH, NCH), 3.33 (3H, s, OCH3), 3.38
(3H, s, OCH3), 3.93 (1H, d, J 13.6, NCH2Ph), 4.40–4.51 (3H, m,
CH OPh, CH(OCH ) ), 5.21 (1H, d, J 17.2, CH᎐CH ), 5.35
᎐
2
3
2
2
1385; δH (270 MHz, CDCl ) 1.75 (3H, s, CH CR᎐CH ), 2.33–
᎐
3
3
2
(1H, d, J 10.5, CH᎐CH ), 5.53 (1H, apparent t, J 7.8, CR ᎐
᎐ ᎐
2 2
2.38 (2H, m, CH2CO2R), 2.78–3.03 (2H, m, NCHCHCH),
3.24–3.36 (1H, m, NCH), 3.67–3.96 (4H, m, NCH, NCO2-
CH), 5.80–5.94 (1H, m, CH᎐CH ), 6.87–6.98 (3H, m, Ar-H),
᎐
2
7.23–7.40 (7H, m, Ar-H); δC (67.9 MHz, CDCl3) 21.4 (CH3),
47.7 (CH2), 53.0 (CH3), 54.6 (CH2), 55.1 (CH3), 62.9 (CH), 66.6
(CH2), 105.7 (CH), 114.6 (CH), 119.7 (CH2), 120.7 (CH), 126.7,
127.9, 128.1, 128.7, 129.4 (5 × CH), 132.2 (CH), 134.3 (C),
140.3 (C), 158.9 (C); m/z (CI) 382 (MHϩ, 100%); HRMS (CI)
[MHϩ] C24H32NO3 requires 382.2382. Found 382.2386 (0.9 ppm
error).
CH ), 4.21–4.56 (3H, m, NCHCH ), 4.73 (1H, br s, CH CR᎐
᎐
3
2
3
CH ), 5.03 (1H, br s, CH CR᎐CH ); m/z (CI) 240 (MHϩ, 50%);
᎐
2
3
2
HRMS (CI) [MHϩ] C12H18NO4 requires 240.1236. Found
240.1235 (0.2 ppm error).
(2R)-N-Benzyl-1,1-dimethoxybut-3-en-2-amine 32
(a) tert-Butyl (1R)-1-(hydroxymethyl)prop-2-enylcarbamate
3125 (505 mg, 2.70 mmol) was dissolved in CH2Cl2 (20 mL) and
Dess–Martin periodinane (1.95 g, 4.60 mmol) was added and
the reaction stirred for 2 h under N2. The solvent was evapor-
(2R,3S,4S)-1-Benzyl-2-(dimethoxymethyl)-3-(iodomethyl)-4-
isopropenylpyrrolidine 34
To diene 33 (166 mg, 0.436 mmol) in dry Et2O (8 mL) at Ϫ50 ЊC
3202
J. Chem. Soc., Perkin Trans. 1, 2000, 3194–3204

View Article Online
under N2 was added Ti(O-i-Pr)4 (162 µL, 0.545 mmol) then
i-PrMgCl (2.0 M in Et2O, 0.52 mL, 1.046 mmol) and the
reaction was allowed to warm to rt. The reaction was stirred for
2 h then cooled to 0 ЊC and iodine [332 mg in Et2O (4 mL),
1.307 mmol] was added. The reaction was stirred for 30 min
then quenched with MeOH (2 mL) and stirred for 2 min
followed by dilution with Et2O (50 mL) and washing with sat.
NaHCO3 (20 mL) then 1 M NaOH (10 mL). The combined
aqueous layers were re-extracted with Et20 (30 mL). The
combined organic layers were then dried (Na2SO4), filtered
and concentrated in vacuo to give the crude product as a
colourless oil which was purified by flash column chromato-
graphy eluting with EtOAc–light petroleum (1:9) to afford the
title compound 34 and starting diene 33 as an inseparable mix-
ture (2:1) (148 mg, 56% 34; 78% based on recovered starting
diene); Rf 0.25 (EtOAc–light petroleum, 1:9); νmax cmϪ1 2930,
1598, 1495, 1112, 1073; δH (270 MHz, CDCl3) 1.86 (3H, s,
[MHϩ] C15H26NO6 requires 316.1760. Found 316.1761 (0.3 ppm
error).
Dimethyl [(2R,3S,4S)-4-isopropenyl-3-(2-methoxy-2-oxoethyl)-
pyrrolidine-1,2-dicarboxylate 36
To acetal 35 (24 mg, 0.076 mmol), in acetone (5 mL) at 0 ЊC was
added Jones’ reagent (0.8 mL) under N2. The reaction was
stirred at the same temperature for 2 h then quenched with
propan-2-ol (2 mL). The reaction was diluted with Et2O (25
mL) and water (5 mL). The aqueous layer was re-extracted
with Et2O (2 × 20 mL) and the combined organic layers were
dried (Na2SO4), filtered and concentrated in vacuo to give the
crude acid as a colourless oil. The crude product was taken up
in MeOH (8 mL), cooled to 0 ЊC, excess ethereal diazomethane
was added and the reaction stirred for 15 min. The excess
diazomethane was blown off with N2 and the solvent was con-
centrated in vacuo to give the crude product as a colourless oil
which was purified by flash column chromatography eluting
with EtOAc–light petroleum (1:2) to afford the title compound
36 (14.8 mg, 65%) as a colourless oil; Rf 0.30 (EtOAc–light
petroleum, 1:2); [α]D ϩ32.8 (c 0.60, CHCl3); νmax cmϪ1 2954,
1754, 1707, 1450, 1386, 1203; δH (270 MHz, CDCl3, mixture of
CH CR᎐CH ), 2.45 (1H, apparent t, J 7.0, NCH CH), 2.69
᎐
3
2
2
(1H, apparent q, J 7.0, NCH2CH), 2.84 (1H, apparent quintet,
J 7.0, CHCH2I), 3.03–3.13 (3H, m, CHCH2I, NCH, NCH2-
CH), 3.20–3.40 (2H, m, CHCH2I, NCH2Ph), 3.45 (3H, s,
OCH3), 3.52 (3H, s, OCH3), 4.37 (1H, d, J 13.8, NCH2Ph), 4.53
(1H, d, J 6.8, CH(OCH ) ), 4.81 (1H, br s, CH CR᎐CH ), 4.94
᎐
3
2
3
2
rotamers) 1.74 (3H, s, CH CR᎐CH ), 2.17–2.27 (1H, m,
᎐
3
2
(1H, br s, CH CR᎐CH ), 7.10–7.31 (5H, m, Ar-H); δ (67.9
᎐
3
2
C
CH2CO2CH3), 2.37–2.50 (1H, m, CH2CO2CH3), 2.79–2.88 (1H,
m, NCHCH), 3.18–3.25 (1H, m, NCH2CH), 3.41–3.60 (1H, m,
NCH2), 3.64 (3H, s, CO2CH3), 3.66 (0.5 × 3H, s, CO2CH3), 3.68
(0.5 × 3H, s, CO2CH3), 3.70 (0.5 × 3H, s, CO2CH3), 3.72
(0.5 × 3H, s, CO2CH3), 3.70–3.79 (1H, m, NCH2), 4.45 (1H,
MHz, CDCl3) 0.41 (CH2), 23.4 (CH3), 46.6, 46.9 (2 × CH), 53.6
(CH3), 54.1 (CH2), 54.7 (CH3), 60.2 (CH2), 68.3 (CH), 105.2
(CH), 113.0 (CH2), 120.2 (CH), 127.7 (CH), 128.9 (CH), 139.8
(C), 142.2 (C); m/z (CI) 416 (MHϩ, 20%); HRMS (CI) [MHϩ]
C18H27NO2I requires 416.1087. Found 416.1089 (0.6 ppm
error).
apparent t, J 6.3, NCH), 4.70 (0.5H, br s, CH CR᎐CH ), 4.73
᎐
3
2
(0.5H, br s, CH CR᎐CH ), 4.98 (1H, br s, CH CR᎐CH );
᎐
᎐
3
2
3
2
δC (67.9 MHz, CDCl3, mixture of rotamers) 22.7 (CH3), 29.4,
29.6 (CH2), 38.2, 39.4 (CH), 47.2, 47.3 (CH), 47.9, 48.0 (CH2),
51.7 (CH3), 52.0, 52.1 (CH3), 52.7 (CH3), 62.7, 62.9 (CH),
113.4, 113.7 (CH2), 140.5, 140.6 (C), 155.2, 155.6 (C), 170.5,
170.8 (C), 172.6 (C); m/z (CI) 300 (MHϩ, 100%); HRMS (CI)
[MHϩ] C14H22NO6 requires 300.1447. Found 300.1447 (0.0 ppm
error).
Methyl [(2R,3S,4S)-2-(dimethoxymethyl)-4-isopropenyl-3-
(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate 35
To alkyl iodide 34 (62.4 mg, 0.150 mmol) contaminated with
diene 33 (28.6 mg, 0.075 mmol) in Et2O (4.5 mL) at Ϫ80 ЊC was
added t-BuLi (1.7 M in pentane, 0.195 mL, 0.331 mmol) and
the reaction was stirred for 3 min under N2. Methyl chloro-
formate (0.2 mL) was added and the reaction was warmed to rt
and stirred for 48 h. The solvent was concentrated in vacuo and
the residue was taken up in Et2O (40 mL) and sat. NaHCO3 (10
mL). The organic layer was separated, dried (Na2SO4), filtered
and concentrated in vacuo to give the crude product as a colour-
less oil which was purified by flash column chromatography
eluting with EtOAc–light petroleum (1:9) to afford the
recovered diene 33 (28.6 mg, 0.075 mmol). Further elution with
EtOAc–light petroleum (1:4→1:1) afforded the title compound
along with the unreacted N-benzyl analogue. The crude mixture
was then dissolved in 1,2-dichloroethane (2 mL) and methyl
chloroformate (0.2 mL) was added and the reaction was heated
at reflux for 2 h. The solvent was concentrated in vacuo and the
residue was taken up in Et2O (40 mL) and sat. NaHCO3 (20
mL). The organic layer was separated, dried (Na2SO4), filtered
and concentrated in vacuo to give the crude product as a colour-
less oil which was purified by flash column chromatography
eluting with EtOAc–light petroleum (1:2) to afford the title
compound 35 (29 mg, 61%) as a colourless oil; Rf 0.10 (EtOAc–
light petroleum, 1:4); [α]D ϩ34.5 (c 0.20, CHCl3); νmax cmϪ1
2925, 1737, 1703, 1450, 1385; δH (270 MHz, CDCl3) 1.73 (3H, s,
Dimethyl [(2S,3S,4S)-4-isopropenyl-3-(2-methoxy-2-oxoethyl)-
pyrrolidine-1,2-dicarboxylate 37
To ester 36 (25 mg, 0.083 mmol) in THF (2 mL) at 0 ЊC was
added LiHMDS (1.0 M in THF, 206 µL, 0.206 mmol) and the
reaction was stirred for 1 h under N2. MeOH (0.5 mL) was
added and the reaction was diluted with Et2O (15 mL) and
NaHCO3 (5 mL). The organic layer was separated, washed with
2 M HCl then dried (Na2SO4), filtered and concentrated in
vacuo to give the crude product as a colourless oil which was
purified by flash column chromatography eluting with EtOAc–
light petroleum (1:2) to afford the title compound 37 (19.7 mg,
80%) as a colourless oil; Rf 0.31 (EtOAc–light petroleum, 1:2);
[α]D Ϫ24.4 (c 0.25, CHCl3) {lit.27 [α]D Ϫ23.8 (c 1.07, CHCl3)};
HRMS (CI) [MHϩ] C14H22NO6 requires 300.1447. Found
300.1447 (0.0 ppm error).
The spectroscopic data were fully consistent with those
reported.27
(؊)-ꢀ-Kainic acid 1
CH CR᎐CH ), 2.16 (1H, dd, J 17.2, 6.1, CH CO R), 2.60–
To ester 37 (30.0 mg, 0.100 mmol) in MeOH (1 mL) was added
40% NaOH (1 mL) and the solution was refluxed for 2 h. The
mixture was cooled and diluted with CH2Cl2 (5 mL) and water
(10 mL). The aqueous layer was filtered through 2 separate ion
exchange columns [Amberlite IRA-45 (OHϪ), H2O then 1 M
HCO2H, and then Amberlite CG-120 (Hϩ), H2O] to give a
white solid which was recrystallised from H2O to give 1 (21.0
mg, 70%) as white needles, mp 244–247 ЊC (decomp.) [lit.23 mp
237–243 ЊC (decomp.)]; [α]D Ϫ15.2 (c 0.95, H2O) {lit.23 [α]D
Ϫ15.0 (c 0.5, H2O)}; HRMS (EI) [Mϩ] C10H15NO4 requires
213.1000. Found 213.0994 (2.8 ppm error).
᎐
3
2
2
2
2.70 (1H, m, CHCH2CO2R), 2.92 (1H, dd, J 17.2, 6.8,
CH2CO2R), 3.17 (1H, apparent quintet, J 6.8, NCH2CH), 3.32
(1H, apparent t, J 10.9, NCH2), 3.41 (3H, s, OCH3), 3.42 (3H, s,
OCH3), 3.63 (3H, s, CO2CH3), 3.66–3.79 (1H, m, NCH2), 3.71
(3H, s, CO2CH3), 4.08 (1H, dd, J 7.0, 4.1, NCH), 4.68 (1H, br s,
CH CR᎐CH ), 4.91 (2H, br s, CH CR᎐CH , CH(OCH ) );
᎐
᎐
3
2
3
2
3 2
δC (67.9 MHz, CDCl3) 23.2 (CH3), 30.5 (CH2), 37.7 (CH), 47.5
(CH), 48.8 (CH2), 51.3 (CH3), 52.4 (CH3), 56.3 (CH3), 58.0
(CH3), 62.3 (CH), 105.6 (CH), 112.9 (CH2), 142.0 (C),
155.9 (C), 173.9 (C); m/z (CI) 316 (MHϩ, 10%); HRMS (CI)
J. Chem. Soc., Perkin Trans. 1, 2000, 3194–3204
3203

View Article Online
The spectroscopic data were fully consistent with those
reported.30
142.4 (CH), 146.5 (C); m/z (CI) 230 (MHϩ, 100%); HRMS (CI)
[MHϩ] C16H24N requires 230.1909. Found 230.1903 (2.5 ppm
error).
cis-1-Benzyl-3-(cyclohex-1-en-1-yl)-4-methylpyrrolidine 39
Acknowledgements
We are grateful to the BBSRC and Roche Discovery Welwyn for
a CASE award (A. D. C.).
Titanium procedure. Dienes 38 (50 mg, 0.144 mmol) were
treated with Ti(O-i-Pr)4 and i-PrMgCl according to the general
procedure outlined for the cyclisation of diene 9. Purification
by column chromatography eluting with MeOH–CH2Cl2 (1:9)
afforded the title compound 39 (19 mg, 52%) as a colourless oil;
Rf 0.20 (MeOH–CH2Cl2, 1:9); νmax cmϪ1 2922, 1494, 1453,
1373; δH (270 MHz, CDCl3) 0.80 (3H, d, J 7.3, CH3), 1.48–1.70
and 1.75–2.05 (8H, m, CH2CH2CH2CH2), 2.19 (1H, dd, J 9.7,
5.6, NCH2CH), 2.43 (1H, m, CH3CH), 2.62 (1H, apparent t,
J 8.7, NCH), 2.77 (1H, apparent q, J 8.7, NCH2CH), 2.92 (1H,
dd, J 8.7, 6.5, NCH), 3.21 (1H, dd, J 9.7, 7.3, NCH), 3.74 (2H,
References
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5 M. Sakai, Takeda Kenkhyusho Nempo, 1960, 19, 27.
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br s, NCH Ph), 5.36 (1H, br s, CH CH᎐CR ), 7.24–7.41 (5H,
᎐
2
2
2
m, Ar-H); δC (67.9 MHz, CDCl3) 15.7 (CH3), 22.6, 22.6, 25.2,
29.4 (4 × CH2), 34.0 (CH), 47.9 (CH), 55.2, 60.8, 61.9 (3 ×
CH2), 122.2 (CH), 127.4, 128.4, 129.1, 129.3 (3 × CH ϩ C),
135.5 (C); m/z (CI) 256 (MHϩ, 100%); HRMS (CI) [MHϩ]
C18H26N requires 256.2065. Found 256.2061 (1.6 ppm error).
cis-1-Benzyl-3-methyl-4-vinylpiperidine 43
9 K. Konno, K. Hashimoto, Y. Ohfune, H. Shirahama and T.
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Titanium procedure. Diene 42 (79 mg, 0.257 mmol) was
treated with Ti(O-i-Pr)4 and i-PrMgCl according to the general
procedure outlined for the cyclisation of diene 9. Purification
by column chromatography eluting with light petroleum–
EtOAc (4:1→1:1) afforded the title compound 43 (32 mg, 58%)
as a colourless oil; Rf 0.25 (light petroleum–EtOAc, 4:1); νmax
cmϪ1 2933, 1638, 1453; δH (270 MHz, d8-toluene, 80 ЊC) 0.92
(3H, d, J 7.0, CH3), 1.45–1.55 and 1.57–1.70 and 1.71–1.82 (3H,
m, NCH2CH2CRHCR2H), 2.01–2.18 (3H, m, RCH2N(Bn)-
CH2R), 2.36 (1H, ddd, J 11.2, 5.6, 1.2, NCH2CH2R), 2.57 (1H,
apparent q, J 5.3, NCH2CH2CR2H), 3.29 (1H, d, J 12.3,
NCH2Ph), 3.37 (1H, d, J 12.3, NCH2Ph), 4.90–5.02 (2H, m,
10 For recent syntheses of kainic acid see: J. Clayden and K.
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14 S. E. Yoo, S. H. Lee, N. Jeong and I. Cho, Tetrahedron Lett., 1993,
34, 3435; O. Miyata, Y. Ozawa, I. Ninomiya and T. Naito, Synlett,
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Melman, J. Org. Chem., 1997, 62, 1896.
15 T. Takahashi, D. Y. Kondakov and N. Suzuki, Organometallics,
1994, 13, 3411.
CRH᎐CH ), 5.81 (1H, ddd, J 17.5, 10.4, 7.0, CRH᎐CH ), 6.98–
᎐
᎐
2
2
7.30 (5H, m, Ar-H); δC (67.9 MHz, CDCl3, cis) 14.6 (CH3), 27.9
(CH2), 33.5 (CH), 42.6 (CH), 52.2 and 58.9 (2 × CH2), 63.3
(CH2), 114.2 (CH2), 126.7 (CH), 128.1 (CH), 128.9 (CH), 138.9
(C), 140.4 (CH); m/z (CI) 216 (MHϩ, 100%); HRMS (CI)
[MHϩ] C15H22N requires 216.1752. Found 216.1751 (0.7 ppm
error).
16 (a) Y. Takayama, Y. Gao and F. Sato, Angew. Chem., Int. Ed. Engl.,
1997, 36, 851; (b) Y. Takayama, S. Okamoto and F. Sato,
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17 Preliminary communication: A. D. Campbell, T. M. Raynham and
R. J. K. Taylor, Chem. Commun., 1999, 245.
(3S,4R)-3-Methyl-1-[(1R)-1-phenylethyl]-4-vinylpiperidine and
(3R,4S)-3-methyl-1-[(1R)-1-phenylethyl]-4-vinylpiperidine 46
and 47
18 J. Barluenga, R.-M. Canteli and J. Flórez, J. Org. Chem., 1994, 59,
Diene 45 (100 mg, 0.312 mmol) was treated with Ti(O-i-Pr)4
and i-PrMgCl according to the general procedure outlined for
the cyclisation of diene 9. Purification by column chromato-
graphy eluting with light petroleum–EtOAc (4:1) afforded the
title compounds 46 and 47 as an inseparable pair of diastereo-
mers (45 mg, 63%, 1:1) as a colourless oil; Rf 0.25 (light
petroleum–EtOAc, 4:1); νmax cmϪ1 2973, 1639, 1452; δH (270
MHz, d8-toluene, 80 ЊC) 1.16 (1.5H, d, J 6.8, NCH2CRHCH3),
1.18 (1.5H, d, J 7.0, NCH2CRHCH3), 1.48 (1.5H, d, J 6.8,
CHCH3), 1.49 (1.5H, d, J 6.8, CHCH3), 1.61–2.08 (3H, m,
NCH2CH2CRHCR2H), 2.25–2.36 (3H, m, RCH2N(CHR)-
CH2R), 2.59–2.72 (1H, m, NCH2CR2H), 2.81 (0.5H, m,
CHCH᎐CH ), 2.94 (0.5H, m, CHCH᎐CH ), 3.50 (0.5H, q,
602.
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᎐
᎐
2
2
J 6.8, NCH), 3.53 (0.5H, q, J 6.8, NCH), 5.13–5.24 (2H, m,
CH᎐CH ), 5.97–6.13 (1H, m, CH᎐CH ), 7.23–7.55 (5H, m,
᎐
᎐
2
2
Ar-H); δC (67.9 MHz, d8-toluene, 80 ЊC) 15.1 and 15.4 (CH3),
19.9 and 20.3 (CH3), 29.3 and 29.4 (CH2), 35.2 (CH), 44.5
(CH), 50.7 and 51.0 (CH2), 57.2 and 58.1 (CH2), 65.8 and 66.0
(CH), 114.9 (CH2), 127.9, 128.9 and 129.5 (3 × CH), 142.3 and
29 B. W. Horrom and H. E. Zaugg, J. Am. Chem. Soc., 1956, 79, 1754.
30 S. Hanessian and S. Ninkovic, J. Org. Chem., 1996, 61, 5418.
3204
J. Chem. Soc., Perkin Trans. 1, 2000, 3194–3204